ADAM9 disintegrin domain activates human neutrophils through an autocrine circuit involving integrins and CXCR2

ADAM9 is a member of the ADAM family whose expression positively correlates with tumor progression. Besides the metalloprotease activity, ADAM9D interacts with different integrins, modulating cell-adhesion events. Previous studies pointed to an important role for neutrophils in tumor development, as the inhibition of neutrophil migration or depletion of this immune cell impairs tumor growth. However, our understanding of the molecular mechanisms involved in this process, as well as the main key players acting on neutrophils, is very limited. Here, we investigated the possible modulatory effects of ADAM9D on human neutrophil functions. Our results show that ADAM9D promotes neutrophil activation and chemotaxis in a process that depends on the engagement of α_vβ₃ and α₉β₁ integrins and on the activation of PI3K/Akt and MAPK signaling pathway. ADAM9D impairs migration of neutrophils toward fMLP, LTB₄, and IL-8 as classic chemoattractants. This effect is blocked by PTX, a G(i)PCR inhibitor. Furthermore, CXCR2 antagonists RPTX and SB225002 also impaired neutrophil chemotaxis in response to ADAM9D, suggesting a hierarchical cross-talk of integrins with CXCR2. Our results indicate that ADAM9D activates neutrophil functions and may be implicated in the inflammatory events associated with cancer and other disorders.